WO2020234114A1 - Nouvelle formulation stable à haute concentration pour anetumab ravtansine - Google Patents
Nouvelle formulation stable à haute concentration pour anetumab ravtansine Download PDFInfo
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- WO2020234114A1 WO2020234114A1 PCT/EP2020/063477 EP2020063477W WO2020234114A1 WO 2020234114 A1 WO2020234114 A1 WO 2020234114A1 EP 2020063477 W EP2020063477 W EP 2020063477W WO 2020234114 A1 WO2020234114 A1 WO 2020234114A1
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- formulation
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- cancer
- anetumab ravtansine
- composition
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Classifications
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Definitions
- the present invention relates to a stable high concentration formulation for the anti- mesothelin immunoconjugate anetumab ravtansine (MF-T-SPDB-DM4).
- the invention is based on the finding that compositions containing anetumab ravtansine (MF-T-SPDB-DM4), which have a certain pH, allow for a long shelf life with less generation of free cytotoxic drugs.
- the invention further relates to an improved method of lyophilization to reduce the primary drying time during said process.
- the lyophilized powder can be reconstituted with water to create a reconstituted solution which is suitable for therapeutic applications. It is a further object to provide a stable reconstituted protein formulation which is suitable for therapeutic administrations.
- the mesothelin precursor polypeptide is a glycophosphatidylinositol (GPI)-anchored, glycosylated cell surface protein that is proteolytically cleaved to a 30 kDa N-terminal secreted polypeptide and a 40 kDa, C-terminal polypeptide, which predominantly occurs in the membrane-bound, GPI-anchored form, and which is named mesothelin herein.
- GPI glycophosphatidylinositol
- Mesothelin is preferentially expressed by certain tumor cells, particularly mesothelioma cells, pancreatic tumor cells and ovarian carcinoma cells, while its expression is limited in normal tissue, making it an attractive target for the development of tumor therapy.
- Anti-mesothelin antibodies including anetumab have been described in W02009/068204A1 , and these antibodies have special features making them very suitable for a use as immunoconjugates.
- An immunoconjugate is composed of an antibody specifically recognizing a target cell antigen, such as a tumor cell antigen, and one or several covalently linked molecules of a drug, particularly a cytotoxic drug such as a maytansinoid.
- Immunoconjugates composed of anti-mesothelin antibodies, antibody fragments, and variants of these antibodies and fragments linked to a chemotherapeutic agent, e.g. maytansinoids, or derivatives thereof have been described in WO2010/124797A1.
- a special highly preferred embodiment of an anti-mesothelin immunoconjugate is anetumab ravtansine (MF-T-SPDB-DM4) described in WO2010/124797A1 in detail.
- ADCs combine the selectivity of an antibody with the efficacy of a cytotoxic compound, connected via a specific linker.
- the stability of an ADC is of utmost importance for the safety and efficacy of the drug.
- the amount of free drug is a critical quality attribute for ADCs.
- the free cytotoxine can damage or kill healthy cells if not conjugated to the antibody (Lin, K. and Tibbitts, J., Pharm Res (2012) 29 (9): 2354). Deconjugation of the drug during storage is possible and can increase the overall drug toxicity.
- strategies that decrease the amount of free drug of an ADC will increase the overall stability.
- Lyophilization is widely used to increase the stability of protein formulations, which are physically and/or chemically unstable in aqueous solutions.
- the four ADCs which have received market approval are all lyophilized.
- the freeze-drying cycle puts additional stress on the protein. If the primary drying time and temperature are not accessed critically, protein collapse may occur which may have an adverse impact on protein stability.
- a suitable formulation for an immunoconjugate prevents chemical and physical instability over a long time period.
- Suitable stable liquid or lyophilized formulations for maytansinoid containing immunoconjugates have been described for example in W02004/004639A2, W02004/110498A2, and W02007/019232A2.
- W02007/019232A2 describes a liquid immunoconjugate formulation comprising several excipients, wherein the formulation is a buffered aqueous solution.
- W02004/110498A2 provides a liquid and a lyophilized composition comprising an antibody chemically coupled to a maytansinoid.
- W02004/004639A2 describes suitable formulations for the immunoconjugate huC242-DM1.
- WO2015/059147A1 provides a liquid and a lyophilized composition for the anti- mesothelin immunoconjugate anetumab ravtansine (MF-T-SPDB-DM4) optimized for low concentration compositions. DESCRIPTION OF FIGURES
- Tg’ [°C] dependency on the MF-T-SPDB-DM4 concentration The glass transition temperature Tg’ [°C] (y axis) is shown as a function of the MF-T-SPDB-DM4 concentration (x axis).
- This invention relates to pharmaceutically suitable compositions / formulations of the immunoconjugate anetumab ravtansine (MF-T-SPDB-DM4).
- Degradation of immunoconjugates is an undesired effect for pharmaceutical applications.
- the efficacy or availability of the drug can change dramatically.
- Degradation can take place due to chemical instability (resulting in a new chemical entity) or physical instability.
- Chemical instability can result from e.g. deamidation, hydrolysis, oxidation, disulfide exchange, or generation of free cytotoxic drugs.
- Physical instability can result from e.g. aggregation or adsorption.
- the conjugation of drugs, especially cytotoxic drugs, which are often hydrophobic, small molecules, to hydrophilic monoclonal antibodies introduces additional instability to immunoconjugates.
- Particle formation in protein pharmaceuticals can destabilize the pharmaceutical compound, thus making the formulation less potent or even harmful for clinical use.
- particles in injected pharmaceutical formulations can cause significant injury in patients.
- formation of aggregates is a major degradation pathway of protein, and may lead to undesirable effects such as immunogenicity.
- MF-T-SPDB-DM4 immunoconjugate anetumab ravtansine
- the present invention is based on the finding that compositions containing anetumab ravtansine (MF-T-SPDB-DM4), which have a certain pH, allow for a long shelf life with less generation of free cytotoxic drugs.
- This formulation allows for long term storage as lyophilized composition (long shelf live) and after reconstitution for the possibility to store the not used portion over a long time period as aqueous solution.
- the present invention is further based on the finding that compositions containing anetumab ravtansine (MF-T-SPDB-DM4), which have a higher protein concentration (equal or more than 15 mg/ml) have an unexpected higher glass transition temperature (Tg’). With higher Tg’ and Tc values, the primary drying temperature can be increased, leading to reduced process times and production costs.
- MF-T-SPDB-DM4 anetumab ravtansine
- Anetumab ravtansine (MF-T-SPDB-DM4) is an antibody-drug conjugate (ADC) comprising the monoclonal antibody MF-T (also known as anetumab) directed against the mesothelin antigen, and the maytansinoid tubulin polymerization inhibitor N2’-deacetyl-N2’ (4-methyl-4-mercapto-1-oxopentyl)-maytansine (termed DM4, CAS Reg. No. 796073-69-3) which are linked via an SPDB- (N-succinimidyl-4-(2-pyridyldithio) butanoate) linker.
- ADC antibody-drug conjugate
- MF-T is an antibody comprising a variable region of the heavy chain (VH) of SEQ ID NO:
- GQGTLVTVSS a variable region of the light chain of SEQ ID NO: 2 (VL : DIALTQPASV SGSPGQSITI SCTGTSSDIG GYNSVSWYQQ HPGKAPKLMI YGVNNRPSGV SNRFSGSKSG
- MF-T is an antibody comprising a region of the heavy chain of SEQ ID NO: 3 (HC:
- anetumab ravtansine antibody-drug conjugates comprise 1 to 6 DM4 drug moieties per antibody (drug-to-antibody ratio).
- a pharmaceutical composition preferentially comprises a mixture of antibody-drug conjugates resulting in an average drug- to-antibody ratio of 2.5 to 4, and even more preferred 2.9 to 3.6.
- anetumab ravtansine is an antibody-drug conjugate of the formula:
- MF-T is the antibody anetumab (MF-T) where the antibody is attached via a lysine residue, and n is 1 to 6.
- Methods for preparation of anetumab ravtansine are disclosed e.g. in WO 2009/068204 (A1) and WO 2010/124797 (A1).
- Methods for the production of maytansinoids and conjugates thereof are disclosed e.g. in WO 2005/020883 (A2), WO 2004/103272 (A2), and WO 2007/024536 (A2).
- the invention provides a formulation / composition suitable for therapeutic applications comprising (i) greater than or equal to 15 mg/ml anetumab ravtansine (MF-T- SPDB-DM4), preferentially about 20 mg/ml anetumab ravtansine, (ii) a buffering system comprising the amino acids L-Histidine and Glycine, (iii) sucrose as a cryoprotectant, and (iv) polysorbate 80 as a surfactant, wherein the composition has a pH of about 4.7 to 5.4.
- Said formulation / composition preferentially has a pH of about 4.7 or 5.1 , and highly preferred has a pH of 5.1.
- the invention provides a lyophilized composition comprising
- anetumab ravtansine (MF-T-SPDB-DM4), (ii) a buffering system comprising the amino acids L-Histidine and Glycine, (iii) sucrose as a cryoprotectant, and (iv) polysorbate 80 as a surfactant, wherein the composition has a pH of about 4.7 to 5.4, highly preferred pH of 5.1 , when reconstituted with water.
- the reconstituted solution of this lyophilized composition comprises greater than or equal to 15 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), preferentially about 20 mg/ml anetumab ravtansine.
- the reconstituted solution of this lyophilized composition is suitable for therapeutic applications.
- the present invention also relates to the administration of pharmaceutical compositions.
- parenteral routes of administration are preferred.
- Methods of parenteral delivery include topical, intra-arterial (directly to the tumor), intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration.
- Formulations of the invention may be administered using an injector, a pump, a syringe, or any other devices known in the art as well as by gravity.
- a needle or a catheter may be used for introducing the formulations of the present invention into the body of a patient via certain parenteral routes.
- compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose, i.e. treatment of a particular disease.
- an effective dose is well within the capability of those skilled in the art.
- the therapeutically effective dose can be estimated initially either in cell culture assays, e.g., neoplastic cells, or in animal models, usually mice, rabbits, dogs, pigs or monkeys. The animal model is also used to achieve a desirable concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
- compositions of this invention are formulated to be acceptable in a therapeutic application.
- “Therapeutic application” refers to treatments involving administration to a subject in need of treatment a therapeutically effective amount of the immunoconjugate anetumab ravtansine (MF-T-SPDB-DM4).
- a “therapeutically effective amount” hereby is defined as the amount of the immunoconjugate anetumab ravtansine (MF-T-SPDB-DM4) that is of sufficient quantity to reduce proliferation of mesothelin positive cell or to reduce size of a mesothelin expressing tumor in a treated area of a subject - either as a single dose or according to a multiple dose regimen, alone or in combination with other agents, which leads to the alleviation of an adverse condition, yet which amount is toxicologically tolerable.
- the subject may be a human or non-human animal (e.g., rabbit, rat, mouse, dog, monkey or other lower-order primate).
- the present invention also relates to methods for treating cancer.
- cancer includes, but is not limited to, cancers of the breast, lung, brain, reproductive organs, digestive tract, urinary tract, liver, eye, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include multiple myeloma, lymphomas, sarcomas, and leukemias.
- breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
- cancers of the respiratory tract include, but are not limited to lung cancer, particularly small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
- brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
- Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
- Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
- Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
- Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
- Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
- liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
- Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi’s sarcoma, melanoma, particularly malignant melanoma, Merkel cell skin cancer, and non melanoma skin cancer.
- Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
- Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
- Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
- Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
- the present invention relates to a method for using the composition / formulation of the present invention, in the treatment or prophylaxis of a cancer, particularly (but not limited to) ovarian cancer, colorectal cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc..
- a cancer particularly (but not limited to) ovarian cancer, colorectal cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc.
- Composition / formulation can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or induce apoptosis, in the treatment or prophylaxis of cancer, in particular (but not limited to) ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc..
- This method comprises administering to a mammal in need thereof, including a human, an amount of a composition / formulation of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc.
- cancer which is effective for the treatment or prophylaxis of cancer, in particular (but not limited to) colorectal cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc..
- treating or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
- the cancer is ovarian cancer, lung cancer, in particular non-small cell lung cancer (NSCLC), pancreatic cancer, or gastric cancer, colorectal cancer , head and neck cancer, bladder cancer, bile duct cancer, breast cancer, cervical cancer, esophageal cancer.
- NSCLC non-small cell lung cancer
- gastric cancer colorectal cancer
- head and neck cancer bladder cancer
- bile duct cancer colorectal cancer
- breast cancer head and neck cancer
- cervical cancer esophageal cancer.
- the exact dosage is chosen by the individual physician in view of the patient to be treated. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Additional factors that may be taken into account include the severity of the disease state, e.g., tumor size and location; age, weight and gender of the patient; diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long acting pharmaceutical compositions might be administered for example every 3 to 4 days, every week, once every two weeks, or once every three weeks, depending on half-life and clearance rate of the particular formulation.
- MF-T-SPDB-DM4 Preferentially anetumab ravtansine (MF-T-SPDB-DM4) is administered every 3 weeks with about 5 to 10 mg/kg, and highly preferred anetumab ravtansine (MF-T- SPDB-DM4) is administered every 3 weeks with 6.5 mg/kg.
- composition comprising anetumab ravtansine (MF-T-SPDB-DM4) of this invention might be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents where the resulting combination causes no unacceptable adverse effects.
- the composition of this invention can be combined with a further component B, i.e. one or more further pharmaceutical agents, such as known anti-angiogenesis, anti-hyper-proliferative, anti-inflammatory, analgesic, immunoregulatory, diuretic, anti-arrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti diabetic or antiviral agents, and the like, as well as with admixtures and combinations thereof.
- Component B can be one or more pharmaceutical agents such as 1311-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basilixima
- component B in combination with a composition / formulation of the present invention will serve to: (1)yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone, (2)provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3)provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans, (5) provide for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments, (7) provide a longer time for tumor progression, and/or (8)yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
- pharmaceutical formulation refers to a preparation suitable for therapeutic applications which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
- pharmaceutical formulation or“formulation” or composition comprising anetumab ravtansine (MF-T-SPDB-DM4) is also called an immunoconjugate formulation.
- the present invention also provides for a lyophilized powder of the liquid formulation.
- “Lyophilized” means that the composition has been freeze-dried under vacuum. During lyophilization the liquid formulation is frozen and the solutes are separated from the solvent. The solvent is removed by sublimation (i.e., primary drying) and next by desorption (i.e. , secondary drying). Lyophilization results in a cake or powder which can be stored over a long time period. Prior to administration the lyophilized composition is reconstituted in solvent, preferentially sterile water for injection. The term "reconstituted formulation”, as used herein, refers to such a lyophilized composition after solubilization. Lyophilization methods are well known in the art (e.g. Wang, W., Int. J . Pharm., 203, 1-60 (2000)). The inventive lyophilized composition was achieved with lyophilization protocols as described in the examples in detail.
- the inventive liquid composition comprises a cryoprotectant.
- the liquid composition prior lyophilization comprises 5 % (w/v) sucrose.
- the lyophilized composition can further contain a bulking agent, preferably a crystallizable bulking agent.
- Bulking agents typically are used in the art to provide structure and weight to the "cake" produced as a result of lyophilization. Any suitable bulking agent known in the art may be used in connection with the inventive lyophilized composition. Suitable bulking agents include, for example, mannitol, dextran, and glycine.
- the inventive composition comprises a surfactant.
- surfactant refers to all detergents comprising a hydrophilic and a hydrophobic portion and includes non-ionic, cationic, anionic, and zwitterionic detergents.
- a non-ionic surfactant is preferred.
- Preferred detergents are for example polysorbate 80 (also known as Tween 80, or polyoxyethylene (20) sorbitan monooleate) or polysorbate 20 (also known as Tween 20, or polyoxyethylene (20) sorbitan monolaurate).
- Most preferably the surfactant is polysorbate 80.
- buffer refers to a buffered solution, which pH changes only marginally after addition of acidic or basic substances. Buffered solutions contain a mixture of a weak acid and its corresponding base, or a weak base and its corresponding acid, respectively.
- buffering system refers to a mixture of one or more of the aforementioned acids and bases.
- a preferred buffering system of this invention contains one or more amino acids. Most preferably the buffering system comprises a mixture of L-Histidine and Glycine.
- a preferred embodiment of the invention is a formulation / composition comprising greater than or equal to 15 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), about 10 mM L- Histidine, about 130 mM Glycine, about 5 % (w/v) sucrose, and about 0.04 % (w/v) polysorbate 80, wherein the formulation is an aqueous solution having a pH of about 4.7 or about 5.1.
- MF-T-SPDB-DM4 anetumab ravtansine
- a preferred embodiment of the invention is a formulation / composition comprising greater than or equal to 15 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), 10 mM L- Histidine, 130 mM Glycine, 5 % (w/v) sucrose, and 0.04 % (w/v) polysorbate 80, wherein the formulation is an aqueous solution having a pH of about 4.7 or about 5.1.
- a preferred embodiment of the invention is a formulation / composition comprising greater than or equal to 15 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), 10 mM L- Histidine, 130 mM Glycine, 5 % (w/v) sucrose, and 0.04 % (w/v) polysorbate 80, wherein the formulation is an aqueous solution having a pH of 4.7 or 5.1.
- a preferred embodiment of the invention is a formulation / composition comprising about 20 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), about 10 mM L-Histidine, about 130 mM Glycine, about 5 % (w/v) sucrose, and about 0.04 % (w/v) polysorbate 80, wherein the formulation is an aqueous solution having a pH of about 4.7 or about 5.1.
- a preferred embodiment of the invention is a formulation / composition comprising 20 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), 10 mM L-Histidine, 130 mM Glycine, 5 % (w/v) sucrose, and 0.04 % (w/v) polysorbate 80, wherein the formulation is an aqueous solution having a pH of about 4.7 or about 5.1.
- a highly preferred embodiment of the invention is a formulation / composition comprising 20 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), 10 mM L-Histidine, 130 mM Glycine, 5 % (w/v) sucrose, and 0.04 % (w/v) polysorbate 80, wherein the formulation is an aqueous solution having a pH of 5.1.
- a highly preferred embodiment of the invention is a formulation / composition comprising 20 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), 10 mM L-Histidine, 130 mM Glycine, 5 % (w/v) sucrose, and 0.04 % (w/v) polysorbate 80, wherein the formulation is an aqueous solution having a pH of 4.7.
- a highly preferred embodiment of the invention is a formulation / composition consisting of 20 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), 10 mM L-Histidine, 130 mM Glycine, 5 % (w/v) sucrose, and 0.04 % (w/v) polysorbate 80, wherein the formulation is an aqueous solution having a pH of 5.1.
- a preferred embodiment of the invention is a lyophilized composition obtained by freeze-drying of the liquid immunoconjugate formulation comprising greater than or equal to 15 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), about 10 mM L-Histidine, about 130 mM Glycine, about 5 % (w/v) sucrose, and about 0.04 % (w/v) polysorbate 80, at a pH of about 4.7 or about 5.1 , or obtainable by freeze-drying of the liquid immunoconjugate formulation comprising greater than or equal to 15 mg/ml anetumab ravtansine (MF-T-SPDB-DM4), about 10 mM L-Histidine, about 130 mM Glycine, about 5 % (w/v) sucrose, and about 0.04 % (w/v) polysorbate 80, at a pH of about 4.7 or about 5.1
- a highly preferred embodiment of the invention is a lyophilized composition obtained by freeze
- a further preferred embodiment of the invention is a formulation / composition comprising anetumab ravtansine (MF-T-SPDB-DM4) mentioned supra for use as a medicament.
- MF-T-SPDB-DM4 anetumab ravtansine
- a further preferred embodiment of the invention is a formulation / composition comprising anetumab ravtansine (MF-T-SPDB-DM4) mentioned supra for use in the treatment of cancer.
- MF-T-SPDB-DM4 anetumab ravtansine
- a further preferred embodiment of the invention is a formulation / composition comprising anetumab ravtansine (MF-T-SPDB-DM4) mentioned supra for use in the treatment of ovarian cancer, lung cancer, in particular non-small cell lung cancer (NSCLC), pancreatic cancer, or gastric cancer, colorectal cancer , head and neck cancer, bladder cancer, bile duct cancer, breast cancer, cervical cancer, esophageal cancer.
- NSCLC non-small cell lung cancer
- gastric cancer colorectal cancer
- head and neck cancer bladder cancer
- bile duct cancer breast cancer
- cervical cancer esophageal cancer
- the invention provides a method of treating cancer comprising administering to a patient in need, thereof an effective amount of formulation / composition comprising anetumab ravtansine (MF-T-SPDB-DM4) mentioned supra.
- a further preferred embodiment is the use of a formulation / composition comprising anetumab ravtansine (MF-T-SPDB-DM4) mentioned supra for use in the manufacture of a medicament for the treatment of cancer.
- MF-T-SPDB-DM4 anetumab ravtansine
- compositions containing comprising anetumab ravtansine were produced. These compositions were subsequently analyzed as described in the following examples.
- the immunoconjugate MF-T-SPDB-DM4 was prepared as described in
- WO2010/124797 To study several formulation compositions the solution comprising the immunoconjugate MF-T-SPDB-DM4 must be changed in a defined way. Solutions comprising MF-T-SPDB-DM4 were buffer exchanged using a 30kDa MWCO Hydrosart Sartocan membrane with the final buffer solution of interest. Sucrose and Polysorbate 80 were added after concentration determination during concentration adjustment.
- This example shows the effect of pH reduction on the stability of the ADC accessed by the free toxophore concentration (RPLC), monomer content (HPLC), drug-to-antibody ratio (DAR; UV), concentration (UV), as well as subvisible particles > 2 pm (MFI) for MF-T- SPDB-DM4.
- RPLC free toxophore concentration
- HPLC monomer content
- DAR drug-to-antibody ratio
- UV concentration
- MFI subvisible particles > 2 pm
- the tested formulation compositions of MF-T-SPDB-DM4 are shown in Table 1.
- the protein concentration was varied between 5, 15 and 20 mg/mL and the pH was altered between 4.7, 5.1 and 5.5.
- the samples were analyzed after 0, 4, 9 and 13 weeks of storage at 25 °C. These experiments try to assess the immunoconjugate stability at non optimal treatment (storage) conditions in the liquid state.
- the free toxophore levels that were generated during storage of the solutions of MF-T-SPDB-DM4 were measured.
- Table 1 MF-T-SPDB-DM4 formulations tested in Example 2.
- the free maytansinoids of the Mesothelin-ADC were determined using RP-HPLC and the results are shown in Table 2.
- the free toxophore concentration increases with increasing storage time. Surprisingly, the concentration of free toxophore was less increased with pH 4.7 and 5.1 compared to 5.5. The three most abundant free drug species found are shown in Table 3. Despite the low levels of free toxophore measured, the levels decrease with decreasing pH for 15 and 20 mg/ml_.
- Maytansinoid 1 is the product of an aminolysis of glycine with DM4. At pH 5.5 the Maytansinoid 1 concentration is twice as high as for pH 5.1 or 4.7.
- DM4-TBA is the hydrolysis product of the linker acid (TBA) with an attached toxophore (DM4).
- TAA linker acid
- DM4 attached toxophore
- Table 3 The most abundant free toxophores and the measured concentration [pg/mg] after storage at 25 °C for 13 weeks.
- compositions for MF-T-SDPB-DM4 with a pH of 5.1 and 4.7 are preferred.
- Anetumab ravtansine 0, 5, 10, 15, 20, 25 mg/mL
- the antibody concentration has a strong effect on the glass transition temperature (Tg’) of the of the free concentrate solution ( Figure 1).
- Tg glass transition temperature
- Figure 1 The antibody concentration has a strong effect on the glass transition temperature (Tg’) of the of the free concentrate solution ( Figure 1).
- Tg glass transition temperature
- Figure 1 At a concentration below 10 mg/mL, the Tg’ is comparable to the placebo solution (0 mg/mL, approx. -35 °C).
- a steep increase in the Tg’ is observed at 315 mg/mL to a Tg’ of approximately -30 °C.
- concentrations higher than 20 mg/mL the Tg’ decreases slightly.
- the significantly increased Tg'values for Anetumab ravtansine in 20 mg/ml_ compared to lower concentrations can reduce the primary drying time as the primary drying temperature can be increased without inducing cake collapse. This can reduce manufacturing times and costs.
- This example shows the robustness of lyophilization and the suitability of the liquid composition for lyophilization.
- the lyophilization methods described above result in a white cake or powder, which can be reconstituted rapidly in water.
- compositions for MF-T-SPDB-DM4 3 15 mg/ml_ are preferred and compositions for MF-T-SPBD-DM4 of 20 mg/ml_ are highly preferred.
Abstract
La présente invention concerne une formulation stable à haute concentration pour l'immunoconjugué anti-mésothéline anetumab ravtansine (MF-T-SPDB-DM4). L'invention repose sur la découverte selon laquelle des compositions contenant de l'anetumab ravtansine (MF-T-SPDB-DM4), qui ont un certain pH, permettent une longue durée de conservation avec une moindre génération de médicaments cytotoxiques libres. L'invention concerne en outre un procédé amélioré de lyophilisation permettant de réduire le temps de séchage primaire pendant ledit procédé. La poudre lyophilisée peut être reconstituée avec de l'eau pour créer une solution reconstituée qui est adaptée à des applications thérapeutiques. La présente invention concerne également une formulation protéique reconstituée stable qui est adaptée à des administrations thérapeutiques.
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